Purpose: The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) would lead to restoration of T cell function in HIV infection. Methods: Eight treatment-naive HIV-infected patients were enrolled who had CD4+ T cell counts between 200 and 500/mm3. After 3 weeks of HAART, the patients were randomized into two groups: 4 patients received cultured allogeneic postnatal thymic tissue at day 42 of HAART and the other 4 were controls. Following 1 week of HAART, patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). Results: HIV plasma RNA levels of 16,625 copies /ml (median) decreased to <100 copies/ml within 12 weeks of therapy in all but one patient. The median increase in CD4+ T cell count over the first 399 days of HAART was 175/mm3. The T cell proliferative responses to Candida antigen and TT normalized in all patients. T cell proliferative responses to KLH developed in 3 of 4 transplant recipients and in 1 of 2 controls (the 2 other controls dropped out) after the secondary immunization. All 4 thymic grafts were rejected. Summary: Four of 6 patients developed T cell proliferative responses to neoantigens over the first 600 days of HAART. Transplanted thymus tissue was rejected. There was with no clear difference in restoration of T cell function in the transplant recipients compared to the controls. Novel immune reconstitution strategies may be needed in those patients on HAART with suboptimal immune restoration. Future plans: We have begun a substudy to evaluate whether rejection of thymus grafts can be prevented by use of a course of immunosuppression prior to thymic transplantation in patients with very low CD4 T cell counts despite over one year of HAART. Significance: It is important to determine how to restore immune function in patients with low T cell counts despite HAART. HIV-infected patients in this category remain at risk for life threatening infections.